Cancer is one of the leading causes of death in the United States. Each year, more than half a million Americans die from cancer and more than one million are newly diagnosed with the disease. Cancer develops from normal tissues through a stepwise accumulation of genetic mutations that causes a cell to escape from its normal growth regulatory mechanisms and proliferate in an uncontrolled manner. Tumor cells can metastasize to secondary sites if treatment of the primary tumor is either incomplete or not initiated before the disease progresses substantially. Early diagnosis and effective treatment of tumors are therefore essential for survival.
Cancer involves the clonal replication of cell populations that have gained a competitive advantage over normal cells through the alteration of regulatory gene expression. Regulatory genes can be broadly classified into two categories including “oncogenes” which, when activated or overexpressed, promote unregulated cell proliferation and “tumor suppressor genes” which, when inactivated or underexpressed, fail to prevent abnormal cell proliferation. A handful of oncogenes have been identified that, when abnormally activated, are involved in the initiation or progression of human cancers. Known oncogenes include, for example, Myc, Ras, Src, and HER2. Similarly, a handful of tumor suppressor genes have been identified that, when inactivated, are involved in the initiation or progression of human cancers. Known tumor suppressor genes include, for example, RB, p53, DCC, APC/MCC, NF1, NF2, WT1, VHL, BRCA1, MST1 and WAF1/CIP1.
In contrast to the small handful of characterized oncogenes and tumor suppressor genes, the recent completion of the human genome sequence has revealed the existence of upwards of 30,000 genes that may contain critical, unidentified oncogenes and tumor suppressor genes. For example, protein kinases are just one family of signaling pathway regulators whose members are known to cause malignant transformation when dysregulated. It is now appreciated that the total complement of human protein kinases is encoded by greater than 500 genes, making them the most populated class of potential druggable cancer targets.
Despite the potential for discovering critical oncogenes and tumor suppressor genes that the human genome has allowed, the route to realizing this potential has been blocked by the fact that most human cancers, particularly epithelial cancers, exhibit global genomic alterations and karyotypic abnormalities that make it difficult to identify specific mutations critical for cell transformation. Moreover, abundant evidence suggests that multiple mutations are required to program the transformed phenotype.
These facts underscore the importance of dissecting the molecular interactions taking place in cells as they develop increasing numbers of mutations. There exists a need, therefore, both to identify novel oncogenes and tumor suppressor genes and to dissect and better characterize the interactions among members of each class.